Mitochondrial voltage-dependent anion channel is responsible for paraquat cytotoxicity.

线粒体电压依赖性阴离子通道是百草枯细胞毒性的原因。

• 批准号: 17591899
• 负责人: SHIMADA Hiroki
• 金额: $ 2.18万
• 依托单位: KANAZAWA MEDICAL UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17591899/
• 关键词: paraquat; mitochondria; cytotoxicity; NADH-quinone oxidoreductasem; voltage-dependent anion channel; superoxide; hydrogen peroxide; NADH; voltage-dependent anion channel; NADH-quinone oxidoreductase_m; permeability transition pore

Paraquat is an herbicide that forms reactive oxygen metabolites, which are toxic to humans. With respect to the cytotoxicmechanisms, we identified a NADH-quinone oxidoreductasem activity located on the mitochondria and propose the participationof a voltage-dependent anion channel, VDAC.When isolated rat mitochondria were incubated with NADH and paraquat, H_2O_2 was produced by NADH-quinoneoxidoreductasem activity of the outer membrane and the mitochondria were damaged. These changes were suppressed bybenzoquinone, 4,4'-diisothiocyanatostilbene-2,29-disulfic acid and anti-VDAC1 antibody. NADH-quinone oxidoreductasemactivity was located by zymography at the 500kDa band on native-polyacrylamide electrophoresis, and it contained VDAC protein in a Western blot. VDAC1-overexpressed HeLa cells treated with paraquat produced more intracellular H_2O_2 thancontrols and were more sensitive to paraquat. In contrast, mitochondria in VDAC1 knockdown cells did not produce H_2O_2 andhad a higher survival rate after exposure to paraquat. The results indicate that mitochondrial VDAC protein was associated with reactive oxygen species that mediated paraquat toxicity.

百草枯是一种除草剂，会形成对人体有毒的活性氧代谢物。在细胞毒作用机制方面，我们发现线粒体上存在NADH-Q氧化还原酶活性，并提出了电压依赖性阴离子通道VDAC的参与。当NADH和百草枯共同孵育大鼠线粒体时，外膜NADH-Q氧化还原酶活性产生H_2O_2，线粒体受到损伤。苯二酚、4，4‘-二异硫氰基二苯乙烯-2，29-二磺酸和抗VDAC1抗体可抑制上述变化。天然聚丙烯酰胺凝胶电泳酶谱在500 kDa处定位NADH-Q氧化还原酶活性，Western印迹分析表明该蛋白含有VDAC蛋白。过表达VDAC1的HeLa细胞经百草枯处理后产生更多的细胞内H_2O_2，且对百草枯更敏感。与之相反，VDAC1基因敲除细胞线粒体不产生H_2O_2，百草枯的存活率较高。结果表明，线粒体VDAC蛋白与介导百草枯中毒的活性氧有关。

项目成果

Furanonaphthoquinones Cause Apoptosis of Cancer Cells by Inducing the Production of Reactive Oxygen Species by the Mitochordrial Voltage-Dependent Anion Channel

呋喃萘醌通过诱导线粒体电压依赖性阴离子通道产生活性氧，导致癌细胞凋亡

• 发表时间: 2006
• 期刊: Cancer Biology ＆ Therapy 5・11
• 作者: Simamura;E.
• 通讯作者: E.

Furanonaphthoquinones Cause Apoptosis of Cancer Cells by Inducing the Production of Reactive Oxygen Species by the Mitochondrial Voltage-Dependent Anion Channel

呋喃萘醌通过诱导线粒体电压依赖性阴离子通道产生活性氧，导致癌细胞凋亡

• 发表时间: 2006
• 期刊: Cancer Biology ＆ Therapy 5
• 作者: Simamura;E.
• 通讯作者: E.